TY - JOUR

T1 - Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark

AU - Stoltze, Ulrik

AU - Skytte, Anne-Bine

AU - Roed, Henriette

AU - Hasle, Henrik

AU - Ejlertsen, Bent

AU - Overeem Hansen, Thomas van

AU - Schmiegelow, Kjeld

AU - Gerdes, Anne-Marie

AU - Wadt, Karin

PY - 2018

Y1 - 2018

N2 - INTRODUCTION: TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.METHODS: We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.RESULTS: We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1-54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300-1,100 expected based on estimated background population frequencies.CONCLUSION: Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.

AB - INTRODUCTION: TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.METHODS: We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.RESULTS: We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1-54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300-1,100 expected based on estimated background population frequencies.CONCLUSION: Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.

KW - Adolescent

KW - Adult

KW - Child

KW - Child, Preschool

KW - Denmark

KW - Female

KW - Genes, p53

KW - Germ-Line Mutation

KW - Humans

KW - Infant

KW - Male

KW - Middle Aged

KW - Pedigree

KW - Registries

KW - Young Adult

U2 - 10.1371/journal.pone.0190050

DO - 10.1371/journal.pone.0190050

M3 - Journal article

C2 - 29324801

VL - 13

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 1

M1 - e0190050

ER -